Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors

Abstract

PCSK9 is present in the circulation in 2 forms: a mature form composed of the PCSK9 prodomain attached to its catalytic domain and a form that is the result of furin cleavage at the Arg218-Gln219 peptide bond. 10,11 Commercially available and proprietary ELISA methods have been capable of measuring Background-The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment. Methods and Results-Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total of 491 incident events (fatal and nonfatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and nonfatal ischemic strokes) were recorded. Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4 compared with quartile 1 was associated with a hazard ratio of 1.69 (95% confidence interval, 1.30-2.19) after adjustment for sex. Further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes mellitus, smoking, overweight, obesity, physical inactivity, and statin use resulted in a decrease in the hazard ratio to 1.48 (95% confidence interval, 1.12-1.95). Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received July 15, 2015; accepted February 12, 2016. Conclusions-Serum Leander et al PCSK9 and Incident Cardiovascular Events 1231total PCSK9 concentrations. 12 Total PCSK9 concentration in the circulation is reportedly influenced by common and rare PCSK9 gene variants, sex, use of statins, and diurnal variation. [13][14][15] Several demographic and metabolic parameters appear to correlate with serum PCSK9, including plasma LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein B (apoB), insulin, glucose, fibrinogen, C-reactive protein, smoking, and body mass index. 13,14 Reported correlations have typically been weak and inconsistent, with the exception of LDL cholesterol, apoB, and triglycerides, for which correlations were weak but consistent. Considering that PCSK9 has convincingly been shown to regulate LDL cholesterol via the LDL receptor, we hypothesized that the serum PCSK9 concentration would be associated with future CVD events. There are to date few published studies examining whether the circulating PCSK9 concentrations can predict CVD risk. Therefore, we undertook the present investigation. Methods Study DesignParticipants in this cohort study were randomly selected f...

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

“…3,4 Recently, it has been discovered that proprotein convertase subtilisin/kexin type 9 has a major role in the regulation of LDL-C, and levels of soluble proprotein convertase subtilisin/kexin type 9 have been identified as a new marker of cardiovascular risk. 5 Although traditionally thought to reduce cardiovascular risk, the role of high-density lipoprotein cholesterol has now been brought into question by negative findings from clinical trials of drugs that increase high-density lipoprotein cholesterol and by negative Mendelian randomization studies. 3,4 In…”

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration and Risk of Cardiovascular Events ― Systematic Review and Meta-Analysis of Prospective Studies ―

“…RR varied from 0.33 to 1.48 across the different studies but only one of the 7 studies showed a significantly positive association between PCSK9 and the risk of CVD events (RR, 1.48; 95% CI: 1.12-1.95; P<0.001). 24 Overall, circulating PCSK9 concentration as a continuous variable was not significantly associated with the risk of CVD events (RR, 1.12; 95% CI: 0.98-1.29, P=0.09). Significant heterogeneity across the studies was observed (I 2 =55.1%, Pheterogeneity=0.038).…”

“…Further, fasting status and type of blood sample (serum or plasma) also differed across the studies, resulting in a large range of mean PCSK9 (94.3-546.5 ng/mL). 24,20 Differences in treatment regimen may have also contributed to the different results. Plasma PCSK9 predicted CVD events in CAD patients with medication alone but not in those with PCI/CABG treatment.…”

“…Study sample size ranged from 443 to 4,232 (total, 10,068). Of the 6 cohort studies, 1 study was conducted in patients with chronic kidney disease, 25 1 among community-based adults, 24 3 in CAD patients, and 1 in male fire- Age, smoking, and HRT.…”

PCSK9 − „missing link“ der familiären Hypercholesterinämie

“…Möglicherweise spielt hier die lebenslang niedrige LDL-Konzentration der Träger der PCSK9-"Loss-offunction"-Mutationen eine kausale Rolle. Hierfür spricht auch die Beobachtung, dass die Plamakonzentration von PCSK9 ein unabhängiger Prädiktor der KHK zu sein scheint [19]. [20,21].…”